Sjögren's syndrome (SjS) is a chronic autoimmune inflammatory disease characterized by lymphocytic infiltration and destruction of lacrimal glands (LG) and salivary gland function (SG). SjS can occur independently (primary SjS) or in conjunction with another autoimmune disease (secondary SjS); both forms may progress to systemic disease of other organs. In both primary and secondary SjS, the presenting symptoms of ocular surface dryness, corneal irritation and increased susceptibility to infection overlap with symptoms of simple keratoconjunctivitis sicca (KCS).
The lacrimal gland (LG) produces most of the proteins present in the ocular surface fluid including growth factors, glycohydrolases, secretory immunoglobulin A, and other anti-infectives. Changes in tear quality and quantity can lead to keratoconjunctivitis sicca (KCS), or dry eye. KCS results from tear deficiency associated with altered LG function or from increased evaporative loss. The most serious cases of tear-deficient KCS are due to Sjogren's syndrome (SjS) and graft-versus-host disease (GVHD); these diseases are characterized by lymphocytic infiltrates in LG and salivary gland (SG) and production of autoantibodies associated with functional quiescence. A principal function of lacrimal gland acinar cells (LGAC) is regulated apical exocytosis of secretory vesicles (SV) containing tear proteins. Within LGAC, proteins destined for apical secretion via regulated exocytosis and proteins destined to function in the lysosomes (Lys) follow the same biosynthetic pathway through the endoplasmic reticulum (ER) and Golgi complex to the trans-Golgi network (TGN). The TGN is the cells' primary nexus for sorting intraluminal, fluid phase and membrane-embedded proteins. For the LG to sustain its primary secretory function, the TGN must sort proteins into the two pathways efficiently and accurately. TGN missorting of secretory proteins would markedly alter the nutrient and protective functions of the tear film. The fidelity of TGN sorting also becomes critical for Lys proteins because so many of these are proteases. If sorted improperly, Lys proteins may hydrolyze cellular autoantigens aberrantly and generate pathogenic epitopes; if they enter exocrine SV they may also damage other proteins being stored for secretion, and then when secreted, damage the cornea or conjunctiva. Evidence from SjS patients for such sorting defects occurring in the TGN of exocrine glands has been reported. While the molecular mechanisms in the LG that mediate the sorting and exocytosis of secretory proteins into tear fluid is yet to be elucidated and characterized, patients with severe SjS or GVDH still require effective therapies. This invention serves to satisfy this need and provide related advantages as well.